Project Summary This application from the Mount Sinai Health System proposes participation as a genetic research center (GRC) within the NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC). IBD genetic discovery has disproportionately focused on European ancestry cohorts, despite high and rising prevalence in all US populations. In Aim 1, participation as a multi- disciplinary GRC in Consortium-wide projects is proposed. Expanding sequence and genotype data on non-European ancestry cohorts is proposed. New analytic methodologies have been developed whereby more ancestrally complex populations, such as Hispanic cohorts, can not only be meaningfully analyzed, but may confer substantial benefits in unlocking the overall genetic architecture of polygenic diseases, such as IBD. The application of novel clinical research tools involving efficient electronic health record and development of more objective endpoints can deepen longitudinal phenotype data for already recruited patients. Given the continued centrality of anti-TNF therapies in an era of multiple new therapies, studies to examine anti-TNF non-response (ileal resection, surgical specimens) and response (new anti- TNF initiation, endoscopically-based) are proposed. Specifically, in Aim 2, definition of intestinal single-cell expression features with anti-TNF non-response and response is proposed using mass cytometry protein analyses (Cytof), and single cell mRNA sequencing. Single cell analyses in IBD tissues shows enormous promise in systematically explicating the precise contributions in the most relevant context of the over 200 genome-wide significant IBD associations. Early single cell analyses points to a highly complex innate immune cell architecture, which may be distinct between various high effect IBD-associated risk alleles of innate immunity. Scaling key results through correlative techniques feasible in larger cohorts, such as using paraffin-embedded tissues and peripheral blood samples is proposed. The advent of multiple new therapies makes this a particularly propitious time to protocolize clinical practice, both to improve patient care, as well as to mine biosamples for IBD research. The insight that is gained through these studies can prioritize genes, cells and pathways from which to scale key results and protocols across the NIDDK IBDGC. The long-term goal of these studies is to efficiently develop protocols to most effectively treat IBD patients, catalyzing the advent of Precision IBD.